Methods for making 3-o-protected morphinones and 3-o-protected morphinone dienol carboxylates

ABSTRACT

Disclosed are methods for making aldehydes and ketones comprising allowing the corresponding primary or secondary alcohol to react in the presence of trichoroisocyanuric acid, a compound of formula R 1 SR 2  and a base. In one embodiment, the alcohol is a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 3  is a protecting group. 
     Also disclosed are methods for making 3-O-protected morphine dienol carboxylates comprising allowing a compound of formula (I) to oxidize in the presence of a chlorine-containing compound and a compound of formula R 1 SR 2 ; and allowing the product of the oxidation step to react with an acylating agent

1. FIELD OF THE INVENTION

The present invention relates to methods for making 3-O-protectedmorphinones and 3-O-protected morphinone dienol carboxylates. Thepresent invention also relates to methods for making aldehydes andketones from the corresponding primary and secondary alcohols,respectively.

2. BACKGROUND OF THE INVENTION

Morphine and structural analogs of morphine (the “morphine alkaloids”)such as codeine, hydrocodone, hydromorphone, naloxone, naltrexone,oxycodone and oxymorphone are used in analgesic prescription drugs.Other morphine analogs, e.g., thebaine, are useful starting materialsfor preparing analgesic morphine alkaloids. However, thebaine is only aminor component of the morphine alkaloids found in the seeds of poppyplants, and synthetic methods for preparing thebaine are relativelycostly (see U.S. Pat. No. 6,262,266 B1 to Chiu et al.).

Codeinone dienol acetate, which is the 3-O-methyl derivative ofmorphinone dienol acetate, is a morphine alkaloid useful for preparinganalgesic and antagonistic morphine alkaloids such as naloxone,naltrexone and oxycodone (see, e.g., U.S. Pat. No. 6,013,796 to Huang etal.). Codeinone dienol acetate can be prepared by oxidation of codeineto codeinone followed by acylation (see, e.g., U.S. Pat. No. 6,013,796to Huang et al.).

Other 3-O-protected-morphinone dienol carboxylates are known and aregenerally prepared by oxidation of the corresponding3-O-protected-morphine followed by acylation. A number of these3-O-protected-morphinone dienol carboxylates have been used to prepareother useful morphine alkaloids.

The following paragraphs relate to known methods for making3-O-protected morphinones by oxidation of the corresponding3-O-protected morphines.

Codeine is 3-O-methylmorphine and codeinone is 3-O-methylmorphinone.

U.S. Pat. No. 2,654,75 to Homeyer et al. describes the reaction ofcodeine with aluminum tri(tert-butoxide) and methoxycylcohexanone intoluene to form codeinone, with yield of codeinone reported to be lessthan 50%.

Ninan et at., Tetrahedron 48:6709-6716 (1992) describes the reaction of3-O-dimethyl-t-butylsilylmorphine with manganese dioxide in chloroformat 25° C. to form 3-O-dimethyl-t-butylsilylmorphinone.

The Ninan et al. reference also describes the reaction of3-O-dimethyl-t-butylsilylmorphine with tetrapropyl ammonium perruthenateand N-methylmorpholine-N-oxide in dichloromethane at an unspecifiedtemperature to form 3-O-dimethyl-t-butylsilylmorphinone in about 86%yield.

U.S. Pat. No. 6,013,796 to Huang et al. describes the reaction of3-O-acetylmorphine with a complex formed of dimethylsulfoxide (“DMSO”)and oxalyl chloride in the presence of base (the “Swern oxidationprocess”) at −78° C. to provide the corresponding 3-acetylmorphinone in73% yield. U.S. Pat. No. 6,013,796 also describes reacting3-O-benzylmorphine under similar conditions to provide3-O-benzylmorphinone in 65% yield. However, the described processrequires at least 2.5 molar equivalents of DMSO per mole of morphine andgenerates malodorous dimethylsulfide as a by-product.

Despite these described methods, there remains a need for improvedmethods for making 3-O-protected morphinones.

The Swern oxidation process described above has been the focus ofconsiderable research, because it avoids the use of aggressive inorganicoxidants such as MnO₂ and is generally useful for oxidizing primary andsecondary alcohols to aldehydes and ketones, respectively. For example,De Luca et al., J. Org. Chem. 66:7907-7909 (2001) describes the reactionof primary or secondary alcohols with a complex formed of DMSO andtrichlorocyanuric acid (“TCCA”) in tetrahydrofuran (“THF”) at −30° C. inthe presence of triethylamine to provide the corresponding aldehydes andketones, respectively. However, malodorous dimethylsulfide is formed asa by-product of the reaction. Accordingly, much effort has been spentmodifying the Swern oxidation process or developing more attractivealternatives.

The following paragraphs relate to known modifications and alternativesto the Swern oxidation processes.

Nishide et al., Tetrahedron. Lett. 43:5177-5179 (2002) describes alow-odor Swern oxidation process using dodecylmethylsulfoxide as thesulfoxide reactant.

Harris et al., J. Org. Chem. 63:2407-2409 (1998) describes a low-odorSwern oxidation process using polymer bound 6-(methylsulfinyl)hexanoicacid as the sulfoxide reactant, and the sulfoxide reactant can beregenerated by reaction of the sulfide by-product with NaIO₄.

An alternative to the Swern reaction is described in Corey et al., J.Am. Chem. Soc. 94:7586-7587 (1972), where a primary or secondary alcoholis reacted with a complex formed of dimethylsulfide andN-chlorosuccinamide (“NCS”) or Cl₂ at −25° C. in the presence of a base(the “Corey-Kim oxidation”) to form the corresponding aldehyde andketone, respectively. However, the Corey reference discloses thatreaction of 2-cyclohexenol forms chlorocyclohexene rather than2-cyclohexenone. Additionally, the described process uses malodorousdimethylsulfide as a reagent.

Ohsugi et al., Tetrahedron 52:8393-8398 (1992) describes a low-odorCorey-Kim oxidation process where a primary or secondary alcohol isreacted with CH₃S(C₁₂H₂₅) and NCS in the presence of triethylamine at−40° C., but the described process uses at least a 3-fold molar excessof the sulfide and NCS per mole of alcohol.

Despite these described methods, there remains a need for improvedmethods for oxidizing primary or secondary alcohols to the correspondingaldehydes or ketones, respectively.

Citation of any reference in Section 2 of this application is not anadmission that the reference is prior art to the application.

3. SUMMARY OF THE INVENTION

The present invention relates to methods for forming an aldehyde orketone from the corresponding primary or secondary alcohol,respectively.

In one embodiment, the invention relates to methods for making a ketone,comprising allowing a secondary alcohol to react in the presence of acompound of formula R₁SR₂, trichloroisocyanuric acid and a base underconditions sufficient to make the ketone, wherein R₁ and R₂ are eachindependently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or -phenyl.

In another embodiment, the present invention relates to methods formaking an aldehyde, comprising allowing a primary alcohol to react inthe presence of a compound of formula R₁SR₂, trichloroisocyanuric acidand a base under conditions sufficient to make the aldehyde, wherein R₁and R₂ are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or-phenyl.

The present invention also relates to methods for making 3-O-protectedmorphinones.

In one embodiment, the invention relates to methods for making acompound of formula (II):

comprising, allowing a compound of formula (I):

to react in the presence of a compound of formula R₁SR₂ and achlorine-containing reagent under conditions sufficient to make thecompound of formula (II), wherein:

R₁ and R₂ are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or-phenyl; and

R₃ is a protecting group.

The present invention also relates to methods for making 3-O-protecteddienol carboxylate derivatives of morphinone.

In one embodiment, the present invention relates to methods for making acompound of formula (III):

comprising:

(a) allowing a compound of formula (I):

to react in the presence of a compound of formula R₁SR₂ and achlorine-containing reagent under conditions sufficient to make amixture comprising a compound of formula (II):

and

(b) allowing the compound of formula (II) to react with a first base andan acylating agent of formula R₄C(O)OC(O)R₄ or R₄C(O)X under conditionssufficient to make the compound of formula (III), wherein:

R₁ and R₂ are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or-phenyl;

R₃ is a protecting group; and

R₄ is —(C₁-C₁₀)alkyl; and

X is —Cl, —Br or —I.

The present invention also relates to novel compositions useful foroxidizing a primary or secondary alcohol to an aldehyde or ketone,respectively.

In one embodiment, the present invention relates to compositionscomprising a compound of formula R₁SR₂, trichloroisocyanuric acid and abase, wherein R₁ and R₂ are each independently —(C₁-C₂₀)alkyl or—(C₃-C₈)cycloalkyl or -phenyl.

The present invention also relates to novel 3-O-protected dienolcarboxylate derivatives of morphinone.

In one embodiment, the present invention relates to compounds of formula(III), wherein:

R₃ is —Si((C₁-C₁₀)alkyl)₃, —si(aryl)(C₁-C₁₀)alkyl)₂, or—Si(aryl)₂(C₁-C₁₀)alkyl); and

R₄ is —(C₁-C₁₀)alkyl.

The present invention can be understood more fully by reference to thefollowing detailed description and illustrative examples, whichexemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1. Definitions

As used herein, the generic phrase “3-O-protected morphine” refers tothe compound having the structure of formula (I):

wherein R₃ is a protecting group.

A compound of formula (Ia) has the structure:

wherein R₃ is a protecting group.

As used herein, the generic phrase “3-O-protected morphinone” refers tothe compound having the structure of formula (II):

wherein R₃ is a -protecting group.

The compound of formula (IIa) has the structure:

wherein R₃ is a protecting group.

As used herein, the generic phrase “3-O-protected morphinone dienolcarboxylate” refers to the compound having the structure of formula(III):

wherein R₃ is a protecting group, and R₄ is a —(C₁-C₁₀)alkyl.

The compound of formula (IlIa) has the structure:

wherein R₃ is a protecting group, and R₄ is a —(C₁-C₁₀)alkyl.

As used herein, the term “halo” refers to —F, —Cl, —Br or —I.

As used herein, the term “—(C₁-C₁₀)alkyl” means a saturatedstraight-chain or branch-chain hydrocarbon having from 1 to 10 carbonatoms. Representative saturated straight chain (C₁-C₁₀)alkyls are-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl,-n-octyl, -n-nonyl and -n-decyl. Representative saturated branched—(C₁-C₁₀)alkyls are -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, andthe like.

As used herein, the term “—(C₁-C₂₀)alkyl” means a saturatedstraight-chain or branched hydrocarbon having from 1 to 20 carbon atoms.Representative saturated straight chain (C₁-C₂₀)alkyls are -methyl,-ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl,-n-nonyl, -n-decyl, -n-undecyl, -n-dodecyl, -n-tridecyl, -n-tetredecyl,-n-pentadecyl, -n-hexadecyl, -n-heptadecyl, -n-octadecyl, -n-nonadecyl,and -n-eicosyl. Non-limiting examples of saturated branched—(C₁-C₂₀)alkyls are -isopropyl, -sec-butyl, -iso-butyl, -tert-butyl, andthe like.

As used herein, the phrase “protecting group” means a group other than-H which is useful for protecting the 3-O-position of the morphine,morphinone and morphinone dienol carboxylate from unwanted reactions.The protecting group can, if desired, be replaced with —H or anothergroup after forming the compound of formula (III).

As used herein, the phrase “anhydrous” when used in reference to anorganic solvent, unless otherwise defined herein, means an organicsolvent having an amount of water that is less than about 0.01% byweight of the total amount of water and organic solvent.

As used herein, the phrase “chlorine-containing reagent” when used inreference to the morphinone-forming method or morphinone-forming steprefers to a compound or complex having a reactive chlorine that isuseful for promoting the formation of the compound of formula (II) fromthe compound of formula (I)

As used herein, the term “isolating” when used in reference to a mixturecomprising a compound of formula (II) or (III) means separating thecompound of formula (II) or (III) from the organic solvent, whenpresent, and water, when present.

4.2. Methods for Oxidizing Primary or Secondary Alcohols

As noted above, the present invention relates to methods for oxidizing aprimary or secondary alcohol to form an aldehyde or ketone, respectively(the “carbonyl-forming method”). Compared to known methods, the presentmethods for oxidizing primary or secondary alcohols can be carried outunder milder conditions and/or with more efficient utilization ofreagents than conventional processes.

In one embodiment, the carbonyl-forming method comprises the use of alow-odor oxidation process.

In one embodiment, the present invention relates to a method for makinga ketone, comprising allowing a secondary alcohol to react in thepresence of a compound of formula R₁SR₂, trichloroisocyanuric acid and abase under conditions sufficient to make the ketone, wherein R₁ and R₂are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or -phenyl.

Non-limiting examples of useful secondary alcohols includestraight-chain and branch-chain alkyl, alkenyl, and alkynyl primaryalcohols including 2-propanol, 2-butanol, 2-pentanol,3-methylbutan-2-ol, 2-hexanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol,3-hexanol, 2-methyl-3-pentanol, 2-heptanol, 3-methyl-2-hexanol,4-methyl-2-hexanol, 5-methyl-2-hexanol, 3-ethyl-2-pentanol,3,3-dimethyl-2-pentanol, 3,4-dimethyl-2-pentanol,4,4-dimethyl-2-pentanol, 3-heptanol, 2-methyl-3-heptanol,4-methyl-3-heptanol, 5-methyl3-heptanol, 2,2-dimethyl-3-pentanol,2,4-dimethyl-3-pentanol, 2-ethyl-3-pentanol, 4-ethyl-3-pentanol,4-heptanol, and the like; cyclic secondary alcohols such ascyclohexanol; the compounds of formula (I) or (Ia) wherein R₃ is aprotecting group; alkylaryl secondary alcohols such as1-phenyl-1-ethanol, 1-phenyl-1-propanol, 1-phenyl-1-propanol, and thelike; dialkyl secondary alcohols such as diphenylmethanol; oligomericand polymeric alcohols such as oligomers and polymers ofpolyvinylalcohol; and the like.

In one embodiment, the carbonyl-forming method comprises the use of acompound of formula (I), wherein R₃ is a protecting group.

In one embodiment, the carbonyl-forming method comprises the use of asecondary alcohol of formula (Ia).

Non-limiting examples of protecting groups useful when thecarbonyl-forming method comprises the compounds of formula (I) include—(C₁-C₁₀)alkyl; -benzyl; acyls such as —C(O)(C₁-C₁₀)alkyl and —C(O)C₆H₅;carbonates such as —C(O)O(C₁-C₁₀)alkyl); silyls such as—Si((C₁-C₁₀)alkyl)₃, —Si(aryl)(C₁-C₁₀)alkyl)₂, and—Si(aryl)₂((C₁-C₁₀)alkyl); phosphineoxides such as —P(O)(CH₃)₂;phosphinesulfides such as —P(S)(CH₃)₂; and arylsulfonates such as—S(O)OC₆H₄-p-CH₃.

In one embodiment, the carbonyl-forming method comprises the use of acompound of formula (I), wherein R₃ is —(C₁-C₁₀)alkyl, -benzyl,—C(O)(C₁-C₁₀)alkyl, —C(O)O(C₁-C₁₀)alkyl), —Si((C₁C₁₀)alkyl)₃,—Si(aryl)((C₁-C₁₀)alkyl)₂, —Si(aryl)₂((C₁-C₁₀)alkyl),—P(O)(C₁-C₁₀)alkyl)₂, —P(S)((C₁-C₁₀)alkyl)₂, or —S(O)OC₆H₄-p-CH₃.

In one embodiment, the carbonyl-forming method comprises the use of acompound of formula (I), wherein R₃ is —CH₃.

In another embodiment, the carbonyl-forming method comprises the use ofa compound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl).

In another embodiment, the carbonyl-forming method comprises the use ofa compound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃.

In another embodiment, the carbonyl-forming method comprises the use ofa compound of formula (I), wherein R₃ is —Si(CH₃)₂(C(CH₃)₃).

In another embodiment, the present invention relates to a method formaking an aldehyde, comprising allowing a primary alcohol to react inthe presence of a compound of formula R₁SR₂, trichloroisocyanuric acidand a base under conditions sufficient to make the aldehyde, wherein R₁and R₂ are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or-phenyl.

Non-limiting examples of primary alcohols useful in the carbonyl-formingmethod include, but are not limited to, straight-chain and branch-chainalkyl, alkenyl, and alkynyl primary alcohols such as methanol, ethanol,n-propanol, n-butanol, 2-methylpropanol, n-pentanol, 2-methylbutanol,3-methylbutanol, n-hexanol, 2-methylpentanol, 3-methylpentanol,4-methylpentanol, 2,2-dimethylbutanol, 2,3-dimethylbutanol,3,3-dimethylbutanol, 2-ethylbutanol, n-heptanol, n-octanol, n-nonanol,n-decanol, and the like.

In one embodiment, the carbonyl-forming method comprises the use of acompound of formula R₁SR₂, wherein R₁ is -methyl and R₂ is—(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or -phenyl.

In another embodiment, the carbonyl-forming method comprises the use ofa compound of formula R₁SR₂, wherein R₁ is —CH₃ and R₂ is—(C₁-C₂₀)alkyl.

In another embodiment, the carbonyl-forming method comprises the use ofa compound of formula R₁SR₂, wherein R₁ is —CH₃ and R₂ is —(C₁₂)alkyl.

The base is an organic base or an inorganic base. Non-limiting examplesof organic bases useful in the carbonyl-forming method include, but arenot limited to, organic amines such as, e.g., trialkylamines such astrimethylamine, triethylamine, tri-n-propylamine, tri-n-butylanaine,diethylmethylamine, dimethylethylamine, diisopropylethylamine, and thelike; aryldialkylamines such as dimethylphenylamine anddiethylphenylamine; pyridine and pyridine substituted with one or more—(C₁-C₄)alkyl such as 2-methylpyridine, 3-methylpyridine,4-methylpyridine, 2,3-dimethylpyridine, 2,4-dimethylpyridine,2,5-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine,2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine,2,4,5-trimethylpyridine, 3,4,5-trimethylpyridine, and the like; pyridinesubstituted with dialkylamino groups such aspara-N,N-dimethylaminopyridine; alkali metal salts of weak acids suchas, e.g., lithium, sodium, potassium, rubidium and cesium carboxylates;and any combination thereof.

Non-limiting examples of inorganic bases useful in the carbonyl-formingmethod include the hydroxides of the alkali metals such as lithium,sodium, potassium, rubidium and cesium.

In one embodiment, the base is an organic base. In another embodiment,the organic base is an organic amine. In another embodiment, the organicamine is triethylamine, diisopropylethylamine, pyridine,dimethylpyridine or dimethylaminopyridine. In another embodiment, theorganic amine is triethylamine.

In another embodiment, the base is an inorganic base.

Compounds of formula (I) and (Ia) are commercially available or can beprepared by methods described in Section 4.3.

Trichloroisocyanuric acid is available from Aldrich Chemical Co.,Milwaukee, Wis.

Compounds of formula R₁SR₂ are commercially available from LancasterSynthesis, Windham, N.H., or can be prepared by reacting a compound offormula R₁SH with K₂CO₃ and R₂I in dimethylformamide as described inOhsugi et al., Tetrahedron 59:8393-8398 (2003).

In one embodiment, the amount of alcohol used in the carbonyl-formingmethod ranges from about 1.0 to about 9.0 molar equivalents per molarequivalent of trichloroisocyanuric acid; in another embodiment, theamount of alcohol used in the carbonyl-forming method ranges from about2.0 to about 5.0 molar equivalents per molar equivalent oftrichloroisocyanuric acid; and in another embodiment, the amount ofalcohol used in the carbonyl-forming method ranges from about 2.0 toabout 4.0 molar equivalents per molar equivalent of trichloroisocyanuricacid.

In one embodiment, the amount of compound of formula R₁SR₂ used in thecarbonyl-forming method ranges from about 1.0 to about 9.0 molarequivalents per molar equivalent of trichloroisocyanuric acid; inanother embodiment, the amount of compound of formula R₁SR₂ used in thecarbonyl-forming method ranges from about 2.0 to about 5.0 molarequivalents per molar equivalent of trichloroisocyanuric acid; and inanother embodiment, the amount of compound of formula R₁SR₂ used in thecarbonyl-forming method ranges from about 2.5 to about 3.5 molarequivalents per molar equivalent of trichloroisocyanuric acid.

In one embodiment, the amount of base used in the carbonyl-formingmethod ranges from about 1.0 to about 15.0 molar equivalents per molarequivalent of trichloroisocyanuric acid; in another embodiment, theamount of base used in the carbonyl-forming method ranges from about 2.0to about 10.0 molar equivalents per molar equivalent oftrichloroisocyanuric acid; and in another embodiment, the amount of baseused in the carbonyl-forming method ranges from about 2.5 to about 7.0molar equivalents per molar equivalent of trichloroisocyanuric acid.

In one embodiment, the carbonyl-forming method is carried out in thepresence of an organic solvent. Non-limiting examples of organicsolvents that are useful in the carbonyl-forming method include, but arenot limited to aromatic hydrocarbons such as benzene, toluene, xylene,mesitylene, chlorobenzene; (C₁-C₄)halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride and dichloroethane;ethers such as diethyl ether, dipropyl ether, dibutyl ether,methyl-tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran; andethyl acetate.

In one embodiment, the organic solvent when used in the carbonyl-formingmethod is benzene, toluene, xylene, mesitylene, chlorobenzene,dichloromethane, chloroform, carbon tetrachloride, dichloroethane,diethyl ether, dipropyl ether, di-butyl ether, methyl-tert-butyl ether,tetrahydrofuran, ethyl acetate, or any combination thereof.

In another embodiment, the organic solvent when used in thecarbonyl-forming method is or includes dichloromethane.

In another embodiment, the organic solvent is or includes toluene.

In one embodiment, the organic solvent when used in the carbonyl-formingmethod is present in an amount ranging from about 0.1 parts by weight upto about 50 parts by weight based on the weight of the compound offormula R₁SR₂ . In another embodiment, the organic solvent when used inthe carbonyl-forming method is present in an amount ranging from about0.1 parts by weight up to about 25 parts by weight based on the weightof the compound of formula R₁SR₂. In another embodiment, the organicsolvent when used in the carbonyl-forming method is present in an amountranging from about 0.1 parts by weight up to about 10 parts by weightbased on the weight of the compound of formula R₁SR₂.

In one embodiment, the organic solvent when used in the carbonyl-formingmethod is anhydrous. Anhydrous organic solvents are commerciallyavailable or can be obtained by contacting the organic solvent with asuitable dehydrating agent such as, e.g., molecular sieves; reactivemetals such as Li, Na or K, and mixtures thereof; metal hydrides such asCaH or LiAlH₄; and metal and metalloid oxides such as BaO, CaO and P₂O₅(see Amarego et al., Purification of Laboratory Chemicals (4th ed.1996); and Gordan et al., The Chemist's Companion 445-447 (1972)). Theamount of water in the organic solvent can be determined by, e.g.,Karl-Fisher titration (see ASTM E1064-00 and ASTM E203-01).

The carbonyl-forming method is carried under conditions that aresufficient to make an aldehyde or ketone. In one embodiment, thecarbonyl-forming method is carried out until at least about 80 molepercent of the alcohol has been converted to an aldehyde or a ketone; inanother embodiment, the carbonyl-forming method is carried out until atleast about 95 mole percent of the alcohol has been converted to analdehyde or a ketone; and in another embodiment, the carbonyl-formingmethod is carried out until at least about 99 mole percent of thealcohol has been converted to an aldehyde or a ketone.

The progress of the carbonyl-forming method can be monitored usingconventional analytical techniques, including, but not limited to,thin-layer chromatography (“TLC”), high-performance liquidchromatography (“HPLC”), gas chromatography (“GC”), gas-liquidchromatography (“GLC”), infrared spectroscopy (“IR”) and nuclearmagnetic resonance spectroscopy (“NMR”) such as ¹H or ¹³C NMR.

Typically, a time that is sufficient to carry out the carbonyl-formingmethod ranges from about 0.25 hours to about 20 hours; in anotherembodiment, a time that is sufficient to carry out the carbonyl-formingmethod ranges from about 0.5 hours to about 10 hours; and in anotherembodiment, a time that is sufficient to carry out the carbonyl-formingmethod ranges from about 1 hours to about 5 hours.

Typically, a temperature that is sufficient to carry out thecarbonyl-forming method ranges from about −78° C. to about 130° C.; inanother embodiment, a temperature that is sufficient to carry out thecarbonyl-forming method ranges from about −50° C. to about 50° C.; andin another embodiment, a temperature that is sufficient to carry out thecarbonyl-forming method ranges from about −40° C. to about 50° C.

The carbonyl-forming method can be carried out at reduced pressure,atmospheric pressure or elevated pressure. In one embodiment, thecarbonyl-forming method is carried out at atmospheric pressure.

In another embodiment, the carbonyl forming step is carried out under aninert atmosphere such as, e.g., N₂, He, Ne, Ar, Kr, Xe, or anycombination thereof. In one embodiment, the carbonyl forming step iscarried out under a N₂ atmosphere.

The order of addition of the compound of formula R₁SR₂,trichloroisocyanuric acid, primary or secondary alcohol, base andorganic solvent, if any, can vary. Examples are as follows.

In one non-limiting embodiment, the carbonyl-forming method is carriedout by adding a primary or secondary alcohol, optionally in the presenceof an organic solvent, to an admixture comprising a compound of formulaR₁SR₂, trichloroisocyanuric acid and a base, optionally in the presenceof an organic solvent.

In another non-limiting embodiment, the carbonyl-forming method iscarried out by adding an admixture comprising a compound of formulaR₁SR₂, trichloroisocyanuric acid and a base, optionally in the presenceof an organic solvent, to a primary or secondary alcohol, optionally inthe presence of an organic solvent.

In another non-limiting embodiment, the carbonyl-forming method iscarried out by adding a base, optionally in the presence of an organicsolvent, to an admixture comprising a compound of formula R₁SR₂ andtrichloroisocyanuric acid, optionally in the presence of an organicsolvent, followed by addition of a primary or secondary alcohol,optionally in the presence of an organic solvent.

In another non-limiting embodiment, the carbonyl-forming method iscarried out by adding an admixture comprising a compound of formulaR₁SR₂ and trichloroisocyanuric acid, optionally in the presence of anorganic solvent, to a base, optionally in the presence of an organicsolvent, followed by addition of a primary or secondary alcohol,optionally in the presence of an organic solvent.

In another non-limiting embodiment, the carbonyl-forming method iscarried out by adding a primary or secondary alcohol, optionally in thepresence of an organic solvent, to an admixture comprising a compound offormula R₁SR₂ and trichloroisocyanuric acid, optionally in the presenceof an organic solvent, followed by addition of a base, optionally in thepresence of an organic solvent.

In another non-limiting embodiment, the carbonyl-forming method iscarried out by adding a compound of formula (I), optionally in thepresence of an organic solvent, to an admixture comprising a compound offormula R₁SR₂ and trichloroisocyanuric acid, optionally in the presenceof an organic solvent, followed by addition of a base, optionally in thepresence of an organic solvent.

In another non-limiting embodiment, the carbonyl-forming method iscarried out by adding a base, optionally in the presence of an organicsolvent, to an admixture comprising a compound of formula R₁SR₂ andtrichloroisocyanuric acid, optionally in the presence of an organicsolvent, followed by addition of a compound of formula (I), optionallyin the presence of an organic solvent.

The aldehyde or ketone formed in the carbonyl-forming method can beisolated and purified by methods known in the art. For example, areaction mixture comprising an aldehyde or ketone can be purified byfractional distillation; chromatography on silica, alumina or FLORISIL™;and/or recystallization. Where the reaction mixture comprising analdehyde or ketone further comprises an organic solvent, all or part ofthe organic solvent can optionally be removed, typically viaevaporation, prior to purification.

Non-limiting examples of organic solvents useful as chromatographyeluents include straight-chain and branch chain aliphatic(C₄-C₁₀)hydrocarbons such as butanes, pentanes, hexanes, heptanes,octanes, nonanes, and decanes; aliphatic cyclic (C₄-C₇)hydrocarbons suchas cyclobutane, cylcopentane, cyclohexane and cycloheptane; aromatichydrocarbons such as benzene, toluene and xylene; each of which can besubstituted with one or more -halo groups.

Other non-limiting examples of organic solvents useful as chromatographyeluents include (C₁-C₄)halogenated hydrocarbons such as chloromethane,methylene chloride, chloroform and carbon tetrachloride;(C₁-C₁₀)aliphatic alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol,n-pentantol, n-hexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, andthe like; dialkyl ethers such as diethyl ether, diisopropyl ether,dibutyl ethers and methyl butyl ethers; diaryl ethers such as diphenylether, cyclic ethers such as tetrahydrofuran and dioxane; glymes such asethylene glycol dimethyl ether, ethyl acetate; dimethylsulfoxide;N-methylpyrrolidinone; hexamethylphosphoramide; dimethylformamide; andany mixture thereof.

In one embodiment, the organic solvent used as chromatography eluentcomprises an aliphatic hydrocarbon and an ether.

The present invention further relates to compositions comprising aprimary or secondary alcohol, a compound of formula R₁SR₂ as definedherein, trichloroisocyanuric acid and a base. These compositions areuseful for making a ketone or an aldehyde, as described above.

Non-limiting examples of primary or secondary alcohols, compounds offormula R₁SR₂, trichloroisocyanuric acid and bases include thosedescribed above for the carbonyl-forming method.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, trichloroisocyanuric acid, a base and acompound of formula (I), wherein R₃ is a protecting group.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, trichloroisocyanuric acid, a base and acompound of formula (I), wherein R₃ is —(C₁-C₁₀)alkyl, -benzyl,—C(O)C₁-C₁₀)alkyl, —C(O)O(C₁-C₁₀)alkyl), −Si((C₁-C₁₀)alkyl)₃,—Si(aryl)((C₁-C₁₀)alkyl)₂, —Si(aryl)₂((C₁-C₁₀)alkyl),—P(O)((C₁-C₁₀)alkyl)₂, —P(S)((C₁-C₁₀)alkyl)₂, or −S(O)OC₆H₄-p-CH₃.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, trichloroisocyanuric acid, a base and acompound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, trichloroisocyanuric acid, a base and acompound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, trichloroisocyanuric acid, a base and acompound of formula (I), wherein R₃ is —Si(CH₃)₂(C(CH₃)₃).

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, trichloroisocyanuric acid, a base and acompound of formula (I), wherein R₃ is —CH₃.

In another embodiment, the compositions comprising a primary orsecondary alcohol, a compound of formula R₁SR₂, and trichloroisocyanuricacid can further comprise an organic solvent. Non-limiting examples oforganic solvents include those described above for the carbonyl-formingmethod.

The relative molar amounts of primary or secondary alcohol, a compoundof formula R₁SR₂, trichloroisocyanuric acid and a base, and the relativeamount of organic solvent, when present, are those described above forthe carbonyl-forming method.

4.3. Methods for Making Morphinones

In another embodiment, the present invention relates to methods formaking a compound of formula (II) (the “morphinone-forming method”)comprising allowing a compound of formula (I) to react in the presenceof a compound of formula R₁SR₂and a chlorine-containing reagent underconditions sufficient to make the compound of formula (II), wherein:

R₁ and R₂ are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or-phenyl; and

R₃ is a protecting group.

In one embodiment, the compound of formula (I) is the compound offormula (Ia), and the compound of formula (II) is the compound offormula (IIa).

In one embodiment, the morphinone-forming method comprises the use of acompound of formula (I), wherein R₃ is —(C₁-C₁₀)alkyl, -benzyl,—C(O)(C₁-C₁₀)alkyl, —C(O)O(C₁-C₁₀)alkyl), —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)((C₁-C₁₀)alkyl)₂, —Si(aryl)₂((C₁-C₁₀)alkyl),—P(O)((C₁-C₁₀)alkyl)₂, —P(S)((C₁-C₁₀)alkyl₂, or —S(O)OC₆H₄-p-CH₃.

In another embodiment, the morphinone-forming method comprises the useof a compound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl).

In another embodiment, the morphinone-forming method comprises the useof a compound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃.

In another embodiment, the morphinone-forming method comprises the useof a compound of formula (I), wherein R₃ is —Si(CH₃)₂(C(CH₃)₃).

In another embodiment, the motphinone-forming method comprises the useof a compound of formula (I), wherein R₃ is —CH₃.

Non-limiting examples of compounds of formula R₁SR₂ useful in themorphinone-forming method include those described in Section 4.2 for thecarbonyl-forming method. In one embodiment, R₁ is —CH₃ and R₂ is—(C₁₂)alkyl.

Non-limiting examples of chlorine-containing reagents useful in themorphinone-forming method include N-chloroamines such astrichloroisocyanuric acid, N-chlorosuccinimide, salts ofdichloroisocyanuric acid such as sodium dichloroisocyanurate,1,3-dichloro-5,5-dimethylhydantoin; Cl₂; and hypochlorites such ascalcium hypochlorite.

In one embodiment, the chloro-containing reagent used in themorphinone-forming method is trichloroisocyanuric acid,N-chlorosuccinimide, sodium dichloroisocyanurate,1,3-dichloro-5,5-dimethylhydantoin, Cl₂, calcium hypochlorite, or anymixture thereof.

In another embodiment, the chloro-containing reagent used in themorphinone-forming method is trichloroisocyanuric acid.

In another embodiment, the chloro-containing reagent used in themorphinone-forming method is N-chlorosuccinimide.

In another embodiment, the chloro-containing reagent used in themotphinone-forming method is Cl₂.

Compounds of formula (I) can be prepared by known methods useful forprotecting a phenolic hydroxy group (see, e.g., Greene et al.,Protective Groups in Organic Synthesis 143-170 (1991), which isincorporated herein by reference).

Compounds of formula (I) where R₃ is —(C₁-C₁₀)alkyl are commerciallyavailable or can be made by allowing morphine to react with ahalo(C₁-C₁₀)alkyl in dimethoxyethane and in the presence oftetraethylammonium fluoride at 20° C. as described in T. W. Greene etal., Protective Groups in Organic Synthesis 146 (1991) and in U.S.Patent Application Publication No. 200310073848 A1.

Compounds of formula (I) where R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl) can be prepared byallowing morphine to react with Na metal or butyllithium, and allowingthe resultant complex to react with ClSi((C₁-C₁₀)alkyl)₃,ClSi(aryl)(C₁-C₁₀)alkyl)₂ or ClSi(aryl)₂(C₁-C₁₀)alkyl) as described inNinan et al., Tetrahedron 48:6709-6716 (1992) and in U.S. Pat. No.6.046,313 to Scheinmann et al. for the synthesis of3-O-dimethyl-t-butylsilylmorphine. Alternatively, the 3-O-silylderivatives of morphine can be prepared by allowing morphine to reactwith ClSi((C₁-C₁₀)alkyl)₃, ClSi(aryl)(C₁-C₁₀)alkyl)₂ orClSi(aryl)₂(C₁C₁₀)alkyl) in a polar organic solvent and in the presenceof base as described in Section 5.1 for the compound of formula (I)where R₃ is —Si(CH₃)₂(C(CH₃)₃).

Compounds of formula (I) where R₃ is —C(O)(C₁-C₁₀)alkyl can be preparedby allowing morphine hydrochloride to react with a compound of formula(C₁-C₁₀)C(O)OC(O)(C₁-C₁₀) in aqueous sodium bicarbonate as described inU.S. Pat. No. 5,908,846 to Bundgaard et al.

Compounds of formula (I) where R₃ is -benzyl can be prepared by allowingmorphine to react with benzylbromide and NaOH in aqueous methanol at 25°C. as described in U.S. Pat. No. 6,013,796 to Huang et al.

Compounds of formula (I) where R₃ is —C(O)O(C₁-C₁₀)alkyl can be preparedby allowing morphine to react with a compound of formulaClC(O)O(C₁-C₁₀)alkyl in chloroform and in the presence of sodiumbicarbonate under refluxing conditions as described in U.S. Pat. No.5,112,975 to Wallace.

Trichloroisocyanuric acid, N-chlorosuccinimide, sodiumdichloroisocyanurate, 1,3-dichloro-5,5-dimethylhydantoin and calciumhypochlorite are available from Aldrich Chemical Co., Milwaukee, Wis.

When Cl₂ is the chlorine-containing reagent, the Cl₂ can be in the formof a gas or solution. The gas form of Cl₂ is available from Matheson,Montgomeryville, Pa., and can be added to the reaction admixture by, forexample, bubbling the Cl₂ into the admixture. The rate and amount of Cl₂addition can be controlled by methods known in the art using, forexample, gas flow regulators and/or meters.

The solution form of Cl₂ can be prepared by allowing gaseous Cl₂ todissolve in a suitable organic solvent. The concentration of Cl₂ in thesolution can be determined by analytical methods known in the art.

Without being limited by theory, Applicant believes that thechlorine-containing reagent reacts with the compound of formula R₁SR₂ toform a sulfonium cation:

The sulfonium compound then reacts with the hydroxyl group of theprimary or secondary alcohol to form the carbonyl group.

In one embodiment, the amount of compound of formula (I) used in themorphinone-forming method ranges from about 1.0 to about 9.0 molarequivalents per molar equivalent of the chlorine-containing reagent; inanother embodiment, the amount of compound of formula (I) used in themorphinone-forming method ranges from about 2.0 to about 5.0 molarequivalents per molar equivalent of the chlorine-containing reagent; andin another embodiment, the amount of compound of formula (I) used in themorphinone-forming method ranges from about 2.0 to about 4.0 molarequivalents per molar equivalent of the chlorine-containing reagent.

In one embodiment, the amount of compound of formula R₁SR₂ used in themorphinone-forming method ranges about 1.0 to about 9.0 molarequivalents per molar equivalent of the chlorine-containing reagent; inanother embodiment, the amount of the compound of formula R₁SR₂ used inthe morphinone-forming method ranges from about 2.0 to about 5.0 molarequivalents per molar equivalent of the chlorine-containing reagent; andin another embodiment, the amount of the compound of formula R₁SR₂ usedin the morphinone-forming method ranges from about 2.5 to about 3.5molar equivalents per molar equivalent of the chlorine-containingreagent.

In one embodiment, the amount of the chlorine-containing reagent used inthe morphinone-forming method ranges from about 1.0 to about 9.0 molarequivalents per molar equivalent of the compound of formula (I); inanother embodiment, the amount of the chlorine-containing reagent usedin the morphinone-forming method ranges from about 2.0 to about 5.0 permolar equivalent of the compound of formula (I); and in anotherembodiment, the amount of the chlorine-containing reagent used in themorphinone-forming method ranges from about 2.0 to about 4.0 per molarequivalent of the compound of formula (I).

In certain embodiments, the morphinone-forming method may furthercomprise the use of a base. Non-limiting examples of useful basesinclude those organic bases and inorganic bases described in Section 4.2for the carbonyl-forming method.

In one embodiment the base is an organic base. In one embodiment, theorganic base is triethylamine or para-N,N-dimethylaminopyridine.

In another embodiment, the base is an inorganic base.

In one embodiment, the amount of base when used in themorphinone-forming method ranges from about 1.0 to about 15.0 molarequivalents per molar equivalent of the chlorine-containing reagent; inanother embodiment, the amount of base when used in themorphinone-forming method ranges from about 2.0 to about 10.0 molarequivalents per molar equivalent of the chlorine-containing reagent; andin another embodiment, the amount of base when used in themorphinone-forming method ranges from about 2.5 to about 7.0 molarequivalents per molar equivalent of the chlorine-containing reagent.

In certain embodiments, the morphinone-forming method may furthercomprise the use of an organic solvent. Non-limiting examples of usefulorganic solvents include those noted above for the carbonyl-formingmethod. In one embodiment, the organic solvent is dichoromethane.

In one embodiment, the organic solvent when used in themorphinone-forming method is present in an amount ranging from about 0.1parts by weight up to about 50 parts by weight based on the weight ofthe compound of formula (I); in another embodiment, the organic solventwhen used in the morphinone-forming method is present in an amountranging from about 0.1 parts by weight up to about 25 parts by weightbased on the weight of the compound of formula (I); and in anotherembodiment, the organic solvent when used in the morphinone-formingmethod is present in an amount ranging from about 0.1 parts by weight upto about 10 parts by weight based on the weight of the compound offormula (I).

In one embodiment, the organic solvent is anhydrous. Methods forpreparing anhydrous solvents are described in Section 4.2 for thecarbonyl-forming method.

The morphinone-forming method is carried under conditions that aresufficient to make the compound of formula (II). In one non-limitingembodiment, the morphinone-forming method is carried out until at leastabout 80 mole percent of the compound of formula (I) has been convertedto the compound of formula (II); in another non-limiting embodiment, themorphinone-forming method is carried out until at least about 95 molepercent of the compound of formula (I) has been converted to thecompound of formula (II); and in another non-limiting embodiment, themorphinone-forming method is carried out until at least about 99 molepercent of the compound of formula (I) has been converted to thecompound of formula (II).

The progress of the morphinone-forming method can be monitored usingconventional analytical techniques comparable to those described inSection 4.2 for monitoring the carbonyl-forming method.

Typically, a time that is sufficient to carry out the morphinone-formingmethod ranges from about 0.25 hours to about 50 hours; in anotherembodiment, a time that is sufficient to carry out the carbonyl-formingmethod ranges from about 0.5 hours to about 25 hours; and in anotherembodiment, a time that is sufficient to carry out themorphinone-forming method ranges from about 1 hours to about 10 hours.

Typically, a temperature that is sufficient to carry out themorphinone-forming method ranges from about −78° C. to about 130° C.; inanother embodiment, a temperature that is sufficient to carry out themorphinone-forming method ranges from about −50° C. to about 50° C.; andin another embodiment, a temperature that is sufficient to carry out themorphinone-forming method ranges from about −40° C. to about 50° C.

The morphinone-forming method can be carried out at reduced pressure,atmospheric pressure or elevated pressure. In one embodiment, themorphinone-forming method is carried out at atmospheric pressure.

In another embodiment, the morphinone-forming method is carried outunder an inert atmosphere such as, e.g., N₂, He, Ne, Ar, Kr, Xe, or anycombination thereof. In one embodiment, the morphinone-forming method iscarried out under a N₂ atmosphere.

The present invention further relates to compositions comprising acompound of formula (I), a compound of formula R₁SR₂ and achlorine-containing compound; wherein R₁ and R₂ are each independently—(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or -phenyl; and R₃ is a protectinggroup. These compositions are useful for making a compound of formula(II).

In another embodiment, the invention relates to compositions comprisinga compound of formula (I), a compound of formula R₁SR₂ and achlorine-containing compound; wherein R₁ and R₂ are each independently—(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or -phenyl; R₃ is a protecting group;and the chlorine-containing reagent is trichloroisocyanuric acid,N-chlorosuccinimide, sodium dichloroisocyanurate,1,3-dichloro-5,5-dimethylhydantoin, Cl₂, calcium hypochlorite, or anymixture thereof.

In another embodiment, the invention relates to compositions comprisinga compound of formula (I), a compound of formula R₁SR₂ and achlorine-containing compound; wherein R₁ and R₂ are each independently—(C₁-C₂₀)alkyl, —C₃-C₈)cycloalkyl or -phenyl; R₃ is a protecting group;and the chlorine-containing reagent is trichloroisocyanuric acid,N-chlorosuccinimide, Cl₂, or any mixture thereof.

In another embodiment, the invention relates to compositions comprisinga compound of formula (I), a compound of formula R₁SR₂ andtrichloroisocyanuric acid; wherein R₁ and R₂ are each independently—(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or -phenyl; and R₃ is a protectinggroup.

In one embodiment, the invention relates to a composition comprising acompound of formula R₁SR₂ as defined herein, a chlorine-containingcompound and a compound of formula (I), wherein is R₃ is —(C₁-C₁₀)alkyl,-benzyl, —C(O)(C₁-C₁₀)alkyl, —C(O)O(C₁-C₁₀)alkyl), −Si((C₁-C₁₀)alkyl)₃,—Si(aryl)((C₁-C₁₀)alkyl)₂, —Si(aryl)₂((C₁-C₁₀)alkyl),—P(O)((C₁-C₁₀)alkyl)₂, —P(S)((C₁-C₁₀e)alkyl)₂, or —S(O)OC₆H₄-p-CH₃.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, a chlorine-containing reagent and acompound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, a chlorine-containing reagent and acompound of formula (I), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, a chlorine-containing reagent and acompound of formula (I), wherein 12.₃ is —Si(CH₃)₂(C(CH₃)₃).

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, a chlorine-containing reagent and acompound of formula (I), wherein R₃ is —CH₃.

In another embodiment, the invention relates to a composition comprisinga compound of formula R₁SR₂, a chlorine-containing reagent and acompound of formula (Ia).

In another embodiment, the compositions comprising a compound of formula(I) or (Ia), a compound of formula R₁SR₂ and a chlorine-containingreagent further comprise a base. Non-limiting examples of bases includethose described in Section 4.2 for the carbonyl-forming method.

In another embodiment, the compositions comprising a compound of formula(I) or (Ia), a compound of formula R₁SR₂ and a chlorine-containingreagent further comprise an organic solvent. Non-limiting examples oforganic solvents include those described in Section 4.2 for thecarbonyl-forming method.

The relative molar amounts of the compound of formula (I) or (Ia), thecompound of formula R₁SR₂, the chlorine-containing reagent, the base, ifany, and the organic solvent, if any, are those described above for themorphinone-forming method.

4.4. Methods for Making 3-O-Protected Morphinone Dienol Carboxylates

As noted above, the present invention also relates to methods for makinga compound of formula (III).

In one embodiment, the present invention relates to a method for makinga compound of formula (III), comprising:

(a) allowing a compound of formula (I) to react in the presence of acompound of formula R₁SR₂ and a chlorine-containing reagent underconditions sufficient to make a compound of formula (II); and (b)allowing the compound of formula (II) to react with a first base and anacylating agent of formula R₄C(O)OC(O)R₄ or R₄C(O)X under conditionssufficient to make the compound of formula (III), wherein

R₁ and R₂ are each independently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl or-phenyl;

R₃ is a protecting group;

R₄ is —(C₁-C₁₀)alkyl; and

X is —Cl, —Br or—I.

The step of allowing a compound of formula (I) to react in the presenceof a compound of formula R₁SR₂ and a chlorine-containing reagent underconditions sufficient to make a compound of formula (II) (the“morphinone-forming step”) can be carried out by the methods describedin Section 4.3 for the morphinone-forming method.

In one embodiment, the morphinone-forming step is carried out in thepresence of a base (the “second base”) as described in Section 4.3 whenthe morphinone-forming method is carried out in the presence of a base.Non-limiting examples of useful second bases include those basesdescribed in Section 4.2 for the carbonyl-forming method. The secondbase, when used in the morphinone-forming step, can be the same as ordifferent from the first base. In one embodiment, the first base and thesecond base, when used, are the same.

In one embodiment, the second base when used in the morphinone-formingstep is triethylamine or para-N,N-dimethylaminopyridine.

In another embodiment, the second base when used in themorphinone-forming step is triethylamine.

In one embodiment, the amount of second base when used in themorphinone-forming step ranges flow about 1.0 to about 15.0 molarequivalents per molar equivalent of the chlorine-containing reagent; inanother embodiment, the amount of second base when used in themorphinone-forming step ranges from about 2.0 to about 10.0 molarequivalents per molar equivalent of the chlorine-containing reagent; andin another embodiment, the amount of second base when used in themorphinone-forming step ranges from about 2.5 to about 7.0 molarequivalents per molar equivalent of the chlorine-containing reagent.

The step of allowing the compound of formula (II) to react with a firstbase and an acylating agent of formula R₄C(O)OC(O)R₄ or R₄C(O)X underconditions sufficient to make the compound of formula (III) (the“morphinone dienol carboxylate-forming step”) can be carried out bymethods described below.

In one embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of a compound of formula (II), wherein R₃ is—(C₁-C₁₀)alkyl, -benzyl, —C(O)(C₁-C₁₀)alkyl, —C(O)O(C₁-C₁₀)alkyl),—Si((C₁-C₁₀ )alkyl)₃. —Si(aryl)((C₁-C₁₀)alkyl)₂,—Si(aryl)₂((C₁-C₁₀)alkyl), —P(O)((C₁-C₁₀)alkyl)₂, —P(S)((C₁-C₁₀)alkyl)₂,or —S(O)OC₆H₄-p-CH₃.

In one embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of a compound of formula (II), wherein R₃ is —CH₃.

In another embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of a compound of formula (II), wherein R₃ is—Si((C₁-C₁₀)alkyl)₃, —Si(aryl)(C₁-C₁₀)alkyl)₂, or—Si(aryl)₂(C₁-C₁₀)alkyl).

In another embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of a compound of formula (II), wherein R₃ is—Si((C₁-C₁₀)alkyl)-₃.

In another embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of a compound of formula (II), wherein R₃ is—Si(CH₃)₂(C(CH₃)₃).

In one embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of an acylating agent of formula R₄C(O)OC(O)R₄.

In another embodiment the morphinone dienol carboxylate-forming stepcomprises the use of an acylating agent of formula CH₃C(O)OC(O)CH₃.

In another embodiment, the morphinone dienol carboxylate-forming methodcomprises an acylating agent of formula R₄C(O)X.

In another embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of an acylating agent of formula R₄C(O)X, wherein X is—F, —Cl, —Br or —I.

In another embodiment, the morphinone dienol carboxylate-forming stepcomprises the use of an acylating agent of formula CH₃C(O)Cl.

Non-limiting examples of first bases useful for the morphinone dienolcarboxylate-forming step include those discussed in Section 4.2 for thecarbonyl-forming method.

In one embodiment, the first base is a trialkylamine,para-N,N-dimethylpyridine or an alkali metal carboxylate.

In another embodiment, the first base is triethylamine.

In another embodiment, the first base is para-N,N-dimethylpyridine.

Acylating agents of formula R₄C(O)OC(O)R₄ or R₄C(O)X are commerciallyavailable or can be prepared by known methods.

In one embodiment, the amount of acylating agent used in the morphinonedienol carboxylate-forming step ranges from about 1 to about 15 molarequivalent per molar equivalent of the compound of formula (II); inanother embodiment, the amount of acylating agent used in the morphinonedienol carboxylate-forming step ranges from about 1 to about 10 molarequivalent per molar equivalent of the compound of formula (II); and inanother embodiment, the amount of acylating agent used in the morphinonedienol carboxylate-forming step ranges from about 2 to about 7 molarequivalent per molar equivalent of the compound of formula (II).

In one embodiment, the amount of first base used in the morphinonedienol carboxylate-forming step ranges from about 1 to about 15 molarequivalents per molar equivalent of the acylating agent; in anotherembodiment, the amount of first base used in the morphinone dienolcarboxylate-forming step ranges from about 2 to about 7 molarequivalents per molar equivalent of the acylating agent; and in anotherembodiment, the amount of first base used in the morphinone dienolcarboxylate-forming step ranges from about 3 to about 6 molarequivalents per molar equivalent of the acylating agent.

In one embodiment, the morphinone dienol carboxylate-forming step iscarried out in the presence of an organic solvent. Non-limiting examplesof useful organic solvents for the morphinone dienol carboxylate-formingstep include those discussed in Section 4.2 for the carbonyl-formingmethod.

In one embodiment, the organic solvent when used in the morphinonedienol carboxylate-forming step is dichloromethane, tetrahydrofuran,methyltetrahydrofuran, toluene, or any mixture thereof.

In one embodiment, the amount of organic solvent when used in themorphinone dienol carboxylate-forming step ranges from about 1 part byweight up to about 100 parts by weight based on the weight of thecompound of formula (II); in another embodiment, the amount of organicsolvent when used in the morphinone dienol carboxylate-forming stepranges from about 5 parts by weight up to about 50 parts by weight basedon the weight of the compound of formula (II); and in anotherembodiment, the amount of organic solvent when used in the morphinonedienol carboxylate-forming step ranges from about 10 parts by weight upto about 25 parts by weight based on the weight of the compound offormula (II).

In one embodiment, the organic solvent when used in the morphinonedienol carboxylate-forming step is anhydrous. Methods for preparinganhydrous organic solvents are described in Section 4.2 for thecarbonyl-forming method.

The morphinone dienol carboxylate-forming step is carried out underconditions that are sufficient to make the morphinone dienolcarboxylate. In one non-limiting embodiment, the morphinone dienolcarboxylate-forming step is carried out until at least about 80 molepercent of the compound of formula (II) has been converted to thecompound of formula (III); in another non-limiting embodiment, themorphinone dienol carboxylate-forming step is carried out until at leastabout 95 mole percent of the compound of formula (II) has been convertedto a compound of formula (III); and in another non-limiting embodiment,the morphinone dienol carboxylate-forming step is carried out until atleast about 99 mole percent of the compound of formula (II) has beenconverted to a compound of formula (III).

The progress of the morphinone dienol carboxylate-forming step can bemonitored using conventional analytical techniques comparable to thosedescribed in Section 4.2

The morphinone dienol carboxylate-forming step is carried out for a timeand at a temperature sufficient to make a compound of formula (III). Inone embodiment, a time sufficient to make a compound of formula (III)ranges from about 1 h up to about 50 h; in another embodiment, a timesufficient to make a compound of formula (III) ranges from about 5 h upto about 30 h; and in another embodiment, a time sufficient to make acompound of formula (III) ranges from about 5 h up to about 25 h.

In one embodiment, a temperature sufficient to make a compound offormula (III) ranges from about −78° C. up to about the boiling point ofthe organic solvent, if used; in another embodiment, a temperaturesufficient to make a compound of formula (III) ranges from about −78° C.up to about the 130° C.; in another embodiment, a temperature,sufficient to make a compound of formula (III) ranges from about 0° C.up to about 100° C.; and in another embodiment, a temperature sufficientto make a compound of formula (III) ranges from about 20° C. up to about75° C.

The morphinone dienol carboxylate-forming step can be carried out atreduced pressure, atmospheric pressure or elevated pressure. In oneembodiment, the morphinone dienol carboxylate-forming step is carriedout at atmospheric pressure.

In one embodiment, the morphinone dienol carboxylate-forming step iscarried out under an inert atmosphere such as, e.g., N₂, He, Ne, Ar, Kr,Xe, or any combination thereof. In another embodiment, the morphinonedienol carboxylate-forming step is carried out under N₂ atmosphere.

In the morphinone dienol carboxylate-forming step, the order of additionof the compound of formula (II), acylating agent, first base and organicsolvent, when present, can vary.

In one non-limiting embodiment, the morphinone dienolcarboxylate-forming step is carried out by adding the compound offormula (II), optionally in the presence of an organic solvent, to anadmixture comprising an acylating agent and a first base, optionally inthe presence of an organic solvent.

In another non-limiting embodiment, the morphinone dienolcarboxylate-forming step is carried out by adding an admixturecomprising an acylating agent and a first base, optionally in thepresence of an organic solvent, to a compound of formula (II),optionally in the presence of an organic solvent.

In another non-limiting embodiment, the morphinone dienolcarboxylate-forming step is carried out by adding a first base,optionally in the presence of an organic solvent, to an admixturecomprising a compound of formula (II), optionally in the presence of anorganic solvent, followed by addition of an acylating agent, optionallyin the presence of an organic solvent.

In another non-limiting embodiment, the morphinone dienolcarboxylate-forming step is carried out by adding an acylating agent,optionally in the presence of an organic solvent, to an admixturecomprising a compound of formula (II), optionally in the presence of anorganic solvent, followed by addition of a first base, optionally in thepresence of an organic solvent.

In one embodiment, the compound of formula (II) is prepared using themorphinone-forming step, and is not isolated before being used in themorphinone dienol carboxylate-forming step.

In another embodiment, the compound of formula (II) is not isolatedafter the morphinone dienol carboxylate-forming step, and the acylatingagent and first base are added to the compound of formula (II), i.e. a“one pot” method.

In another embodiment, the compound of formula (II) is not isolatedafter the morphinone-forming step, and the acylating agent and firstbase are added simultaneously to the compound of formula (II).

In another embodiment, the compound of formula (II) is not isolatedafter the morphinone-forming step, and the acylating agent is addedfirst to the compound of formula (II) followed by addition of the firstbase.

In another embodiment, the compound of formula (II) is not isolatedafter the morphinone-forming step, and the first base is added first tothe compound of formula (II) followed by addition of the acylatingagent.

In another embodiment, the morphinone-forming step further comprises asecond base; the compound of formula (II) is not isolated after themorphinone-forming step; and the acylating agent is added to thecompound of formula (II) followed by addition of the first base.

In another embodiment, the morphinone-forming step further comprises asecond base; the compound of formula (II) is not isolated after themorphinone-forming step; and the acylating agent and first base areadded simultaneously to the compound of formula (II); wherein the secondbase and first base are the same.

In one embodiment, the compound of formula (II) is not isolated afterthe morphinone-forming step, and the morphinone-farming step comprisesthe use of a first base and a second base. When the morphinone-formingstep comprises the use of a first base and a second base, the first baseand second base can be the same or different. In one embodiment, thefirst base and second base are the same. In another embodiment, thefirst base and second base are both triethylamine.

In another embodiment, the compound of formula (II) is isolated prior toits use in the morphinone dienol carboxylate-forming step. Methods forisolating the compound of formula (II) include those discussed inSection 4.2 for the ketones or aldehydes formed in the carbonyl-formingmethod.

If desired, compounds of formula (III) can be isolated and purified bymethods comparable to those discussed in Section 4.2 for isolating andpurifying the ketones or aldehydes formed in the carbonyl-forming methodand/or by methods described below.

In one embodiment, a method for isolating a compound of formula (III)comprises contacting the compound of formula (III) with an organicsolvent and water.

For example, the compound of formula (III) can be isolated by contactingan admixture (the “contacting step”) comprising the compound of formula(III) and an organic solvent with water that is optionally acidified.When the water used in the contacting step is not acidified, the organicphase is collected, the aqueous phase can be further contacted withorganic solvent, and the resultant biphasic admixture can optionally befurther treated with a base such as 25% aqueous NaOH to increase the pHof the aqueous phase to within the range of about 7.0 to about 9.0.

When the water used in the contacting step is acidified, the aqueousphase is collected; the aqueous phase is contacted with an organicphase; the resultant biphasic admixture is further treated with a basesuch as 25% aqueous NaOH to increase the pH of the aqueous phase towithin the range of about 7.0 to about 9.0; and the organic phase iscollected.

The combined organic phases are concentrated to a residue under reducedpressure, and the resultant residue can be further isolated and purifiedby methods comparable to those described above in Section 4.2 such as,e.g., distillation, crystallization and/or chromatography.

Non-limiting examples of useful organic solvents for contacting acompound of formula (III) in the presence of water includewater-immiscible organic solvents such as straight-chain andbranch-chain aliphatic (C₄-C₁₀)hydrocarbons such as butanes, pentanes,hexanes, heptanes, octanes, nonanes, decanes; cyclic aliphatic(C₄-C₇)hydrocarbons such as cyclobutane, cyclopentane, cyclohexane andcycloheptane; aromatic hydrocarbons such as benzene, toluene and xylene,each of which can be substituted with one or more -halo or -hydroxygroups; (C₁-C₃)hydrocarbons substituted with two or more -halo groupssuch as dichloromethane, chloroform and carbon tetrachloride; dialkylethers such as diethyl ether, diisopropyl ether, dibutyl ethers andmethyl butyl ethers; ethyl acetate; and any mixture thereof. In oneembodiment, the organic solvent is dichloromethane.

Compounds of formula (III) are useful for making morphine alkaloids suchas naloxone, naltrexone and oxycodone by methods known in the art (see,e.g., U.S. Pat. No. 6,013,796 to Huang et al.).

If desired, the R₃ protecting group of the compound of formula (III) canbe removed and replaced with a group such as —H (the “deprotectionstep”). Typically, the deprotection step is not carried out untilcompleting other chemical processes that might be adversely affected bythe presence of a hydroxyl group on the benzylic ring of the morphinealkaloid. Methods for removing specific protecting groups from morphinealkaloids are described, e.g., in U.S. Pat. No. 4,472,253 to Schwartz(where R₃ is -alkyl); U.S. Pat. No. 5,112,975 to Wallace (where 12₃ is-carbonate); and U.S. Pat. No. 6,008,355 to Huang et al. (where R₃ is-acyl); or by methods known in the art for deprotecting phenols (see,e.g., Greene et al., Protective Groups in Organic Synthesis 143-170(1991), each reference being incorporated herein by reference).

As noted above, the present invention also relates to novel compounds offormula (III), wherein R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl; and R₄ is—(C₁-C₁₀)alkyl.

In one embodiment, the present invention relates to novel compounds offormula (III), where R₃ is —Si((C₁-C₁₀)alkyl)₃.

In another embodiment, the present invention also relates to novelcompounds of formula (III), where R₃ is —Si(CH₃)₂(C(CH₃)₃).

In another embodiment, the present invention also relates to novelcompounds of formula (III), where R₄ is —CH₃.

The novel compounds of formula (III) can be prepared by allowing acompound of formula (II), where R₃ is —Si((C₁-C₁₀)alkyl)₃,—Si(aryl)(C₁-C₁₀)alkyl)₂, or —Si(aryl)₂(C₁-C₁₀)alkyl) to react with afirst base and an acylating agent under conditions sufficient to makethe compound of formula (III) as described above.

The following examples are set forth to assist in understanding theinvention and do not limit the invention described and claimed herein.Such variations of the invention, including the substitution of allequivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulations orminor changes in experimental design, fall within the scope of thepresent invention.

5. EXAMPLES 5.1. Example 1 Synthesis of3-O-Bis(Dimethyl-T-Butyl)Silylmorphine

A solution of dimethyl-t-butylsilylchloride (0.115 g, 0.76 mmol) intetrahydrofuran (76 mL) (Aldrich) was added over about 5 min to asolution of morphine base (20.38 g, 71 mmol), imidazole (14.59 g; 214mmol) and dimethylformamide (“DMF”) (100 ml) at 25° C. under N₂atmosphere. The resultant green solution was stirred at 25° C. for 24 hand concentrated under reduced pressure and at 40° C. The resultantviscous mixture was added to deionized water (500 g) at 25° C., and theresultant white precipitate was collected via filtration. The solidswere dissolved in dichloromethane (100 ml), and the resultant organicphase was collected. The organic phase was dried over sodium sulfate,filtered, and the filtrate concentrated under reduced pressure at 40° C.The resultant residue was recrystallized from boiling heptane (75 ml) toafford 3-O-bis(dimethyl-t-butyl)silylmorphine as white crystals. Yield:13.60 g (34 mmol, 48%).

5.2. Example 2 One-Pot Synthesis of Codeinone Dienol Acetate

Preparation of Codeinone: Trichloroisocyanuric acid (2.30g, 3.8 mmol)was charged to a 100 ml round-bottom flask equipped with a distillationhead, and the contents of the flask were cooled to −30° C. under an N₂atmosphere. Anhydrous dichloromethane (15 ml) was charged to the flask,and the resultant suspension was stirred for 30 min at −30° C. Asolution of codeine (2.97 g, 9.9 mmol) in anhydrous dichloromethane (15ml) was added drop-wise over about 5 min to the suspension, and thecontents of the flask were mixed for about 30 min at −30° C. Theresultant milky suspension was maintained at −30° C., and neattriethylamine (6.91 ml, 50 mmol) was added drop-wise over about 10 min.The resultant light brown suspension was warmed to 10° C. over 2 h atwhich time the conversion of codeine to codeinone was complete.

Preparation of Codeinone Dienol Acetate: The brown suspension from abovewas allowed to warm to room temperature, and neat acetic anhydride (4.68ml, 50 mmol) was added. The contents of the flask were warmed to about50° C., and about 90% of the dichloromethane was removed bydistillation. The resultant slurry was allowed to cool to about 25° C.and mixed for 17 h at 25° C. at which time the conversion of codeinoneto codeinone dienol acetate was complete.

Dichloromethane (20 ml) was added to the reaction mixture and themixture cooled to 0° C. A solution of 3 ml of 88% (w/w) formic acid in20 ml of water at about 0° C. was added to the cooled mixture, and thebiphasic mixture was agitated for 5 min at 0° C. The resultant organicphase was collected and washed with a solution 1 ml of 88% (w/w) formicacid in 20 ml of water. The aqueous layers were combined and cooled toabout 0° C. Dichloromethane (20 ml) was added, then 25% (w/w) aqueoussodium hydroxide was added until the pH of the aqueous phase was 8.75.The aqueous layer was collected, and extracted with dichloromethane (20ml). The combined organic layer were dried over sodium sulfate,filtered, and concentrated under reduced pressure at 30° C. Theresultant oily residue was further dried at 40 Torr at 30° C. to providecodeinone dienol acetate as a light brown solid. Yield: 2.82 g (83 mmol;84%).

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

What is claimed is:
 1. A method for making an aldehyde, comprisingallowing a primary alcohol to react in the presence of a compound offormula R₁SR₂, trichloroisocyanuric acid, and a base under conditionssufficient to make the aldehyde, wherein R₁ and R₂ are eachindependently —(C₁-C₂₀)alkyl, —(C₃-C₈)cycloalkyl, or -phenyl.
 2. Themethod of claim 1, wherein the amount of base ranges from about 1.0 toabout 15.0, from about 2.0 to about 10.0, or from about 2.5 to about 7.0molar equivalents per molar equivalent of trichloroisocyanuric acid. 3.The method of claim 1, wherein the base is selected from triethylamine,diisopropylethylamine, pyridine, dimethylpyridine,dimethylaminopyridine, and any mixture thereof.
 4. The method of claim3, wherein the base is triethylamine.
 5. The method of claim 3, whereinthe amount of base ranges from about 1.0 to about 15.0, from about 2.0to about 10.0, or from about 2.5 to about 7.0 molar equivalents permolar equivalent of trichloroisocyanuric acid.
 6. The method of claim 1,wherein R₁ is —CH₃ and R₂ is —(C₁-C₂₀)alkyl.
 7. The method of claim 6,wherein R₁ is —CH₃ and R₂ is —(C₁₂)alkyl.
 8. The method of claim 7,wherein the amount of base ranges from about 1.0 to about 15.0, fromabout 2.0 to about 10.0, or from about 2.5 to about 7.0 molarequivalents per molar equivalent of trichloroisocyanuric acid.
 9. Themethod of claim 7, wherein the base is selected from triethylamine,diisopropylethylamine, pyridine, dimethylpyridine,dimethylaminopyridine, and any mixture thereof.
 10. The method of claim9, wherein the base is triethylamine.
 11. The method of claim 9, whereinthe amount of base ranges from about 1.0 to about 15.0, from about 2.0to about 10.0, or from about 2.5 to about 7.0 molar equivalents permolar equivalent of trichloroisocyanuric acid.
 12. The method of claim7, wherein the amount of the compound of formula R₁SR₂ ranges from about1.0 to about 9.0, from about 2.0 to about 5.0, or from about 2.5 toabout 3.5 molar equivalents per molar equivalent of trichloroisocyanuricacid.
 13. The method of claim 12, wherein the amount of base ranges fromabout 1.0 to about 15.0, from about 2.0 to about 10.0, or from about 2.5to about 7.0 molar equivalents per molar equivalent oftrichloroisocyanuric acid.
 14. The method of claim 12, wherein the baseis selected from triethylamine, diisopropylethylamine, pyridine,dimethylpyridine, dimethylaminopyridine, and any mixture thereof. 15.The method of claim 14, wherein the base is triethylamine.
 16. Themethod of claim 14, wherein the amount of base ranges from about 1.0 toabout 15.0, from about 2.0 to about 10.0, or from about 2.5 to about 7.0molar equivalents per molar equivalent of trichloroisocyanuric acid. 17.The method of claim 1, wherein the amount of the compound of formulaR₁SR₂ ranges from about 1.0 to about 9.0, from about 2.0 to about 5.0,or from about 2.5 to about 3.5 molar equivalents per molar equivalent oftrichloroisocyanuric acid.
 18. The method of claim 17, wherein theamount of base ranges from about 1.0 to about 15.0, from about 2.0 toabout 10.0, or from about 2.5 to about 7.0 molar equivalents per molarequivalent of trichloroisocyanuric acid.
 19. The method of claim 17,wherein the base is selected from triethylamine, diisopropylethylamine,pyridine, dimethylpyridine, dimethylaminopyridine, and any mixturethereof.
 20. The method of claim 19, wherein the base is triethylamine.21. The method of claim 19, wherein the amount of base ranges from about1.0 to about 15.0, from about 2.0 to about 10.0, or from about 2.5 toabout 7.0 molar equivalents per molar equivalent of trichloroisocyanuricacid.
 22. The method of claim 1, wherein the primary alcohol is astraight-chain alkyl primary alcohol, a straight-chain alkenyl primaryalcohol, a straight-chain alkynyl primary alcohol, a branch-chain alkylprimary alcohol, a branch-chain alkenyl primary alcohol, or abranch-chain alkynyl primary alcohol.
 23. The method of claim 1, whereinthe primary alcohol is methanol, ethanol, n-propanol, n-butanol,2-methylpropanol, n-pentanol, 2-methylbutanol, 3-methylbutanol,n-hexanol, 2-methylpentanol, 3-methylpentanol, 4-methylpentanol,2,2-dimethylbutanol, 2,3-dimethylbutanol, 3,3-dimethylbutanol,2-ethylbutanol, n-heptanol, n-octanol, n-nonanol, or n-decanol.
 24. Themethod of claim 1, wherein the amount of primary alcohol ranges fromabout 1.0 to about 9.0, from about 2.0 to about 5.0, or from about 2.0to about 4.0 molar equivalents per molar equivalent oftrichloroisocyanuric acid.
 25. The method of claim 1, wherein thereacting occurs in a solvent selected from aromatic hydrocarbons,(C₁-C₄)halogenated hydrocarbons, ethers, glymes, ethyl acetate, and anymixture thereof.
 26. The method of claim 25, wherein the solvent isselected from benzene, toluene, xylene, mesitylene, chlorobenzene,dichloromethane, chloroform, carbon tetrachloride, dichloroethane,diethyl ether, dipropyl ether, di-butyl ether, methyl-tert-butyl ether,tetrahydrofuran, ethylene glycol dimethyl ether, ethyl acetate, and anymixture thereof.
 27. The method of claim 25, wherein the solventcomprises toluene, dichloromethane, or any mixture thereof.